Orofacial clefts (OFCs) affects one out of every 700 infants born worldwide and are some of the most common birth defects in humans. Investigations into the genetic and molecular etiology of OFC is an essential pre- requisite for prevention and will have a huge impact on financial, educational, medical, psychological, and cultural problems associated with OFCs—leading to significant public health benefits. We have made reasonable progress in human OFC genetics through seven Genome Wide Association Studies (GWAS) for CL/P, three meta-analyses for CL/P, three GWAS for cleft palate only (CPO), and two Whole Genome Sequencing (WGS) study identifying over 60 risk loci and several de novo variants. The proposed specific aims will allow us to identify and test both common and rare genetic variants that elevate risk for CL/P, and to identify genetic variants associated with specific OFC phenotypes in the population that has accumulated the greatest genetic variation in the human race. The use of whole-genome sequencing to identify rare functional variants is expected to substantially expand the findings from the few exome studies of OFC that have been conducted. We hypothesize that bilateral complete cleft lip and palate(BCLP), the most clinically severe form of OFC, is associated with a higher mutation load than less severe forms and focusing on BCLP will facilitate the discovery of novel risk variants. This approach is robust in that we are using a clinically homogeneous cohort in order to minimize genetic heterogeneity and increases the likelihood of discovering genetic factors for BCLP. This application will be led by Dr Butali as Principal Investigator. He will collaborate with Dr. Taub at John Hopkins University and Dr. Adeyemo at the NHGRI. Collectively, the experimental design and approach, the PI and co-Is, and the environment outlined in this proposal provide the catalyst to improve oral and craniofacial health.